Specific processing of tenascin-C by the metalloprotease meprinbeta neutralizes its inhibition of cell spreading

The metalloprotease meprin has been implicated in tissue remodelling due to its capability to degrade extracellular matrix components. Here, we investigated the susceptibility of tenascin-C to cleavage by meprinbeta and the functional properties of its proteolytic fragments. A set of monoclonal antibodies against chicken and human tenascin-C allowed the mapping of proteolytic fragments generated by meprinbeta. In chicken tenascin-C, meprinbeta processed all three major splicing variants by removal of 10kDa N-terminal and 38kDa C-terminal peptides, leaving a large central part of subunits intact. A similar cleavage pattern was found for large human tenascin-C variant where two N-terminal peptides (10 or 15kDa) and two C-terminal fragments (40 and 55kDa) were removed from the intact subunit. N-terminal sequencing revealed the exact amino acid positions of cleavage sites. In both chicken and human tenascin-C N-terminal cleavages occurred just before and/or after the heptad repeats involved in subunit oligomerization. In the human protein, an additional cleavage site was identified in the alternative fibronectin type III repeat D. Whereas all these sites are known to be attacked by several other proteases, a unique cleavage by meprinbeta was located to the 7th constant fibronectin type III repeat in both chicken and human tenascin-C, thereby removing the C-terminal domain involved in its anti-adhesive activity. In cell adhesion assays meprinbeta-digested human tenascin-C was not able to interfere with fibronectin-mediated cell spreading, confirming cleavage in the anti-adhesive domain. Whereas the expression of meprinbeta and tenascin-C does not overlap in normal colon tissue, inflamed lesions of the mucosa from patients with Crohn's disease exhibited many meprinbeta-positive leukocytes in regions where tenascin-C was strongly induced. Our data indicate that, at least under pathological conditions, meprinbeta might attack specific functional sites in tenascin-C that are important for its oligomerization and anti-adhesive activity.

The substrate degradome of meprin metalloproteases reveals an unexpected proteolytic link between meprin β and ADAM10.

The in vivo roles of meprin metalloproteases in pathophysiological conditions remain elusive. Substrates define protease roles. Therefore, to identify natural substrates for human meprin α and β we employed TAILS (terminal amine isotopic labeling of substrates), a proteomics approach that enriches for N-terminal peptides of proteins and cleavage fragments. Of the 151 new extracellular substrates we identified, it was notable that ADAM10 (a disintegrin and metalloprotease domain-containing protein 10)-the constitutive α-secretase-is activated by meprin β through cleavage of the propeptide. To validate this cleavage event, we expressed recombinant proADAM10 and after preincubation with meprin β, this resulted in significantly elevated ADAM10 activity. Cellular expression in murine primary fibroblasts confirmed activation. Other novel substrates including extracellular matrix proteins, growth factors and inhibitors were validated by western analyses and enzyme activity assays with Edman sequencing confirming the exact cleavage sites identified by TAILS. Cleavages in vivo were confirmed by comparing wild-type and meprin(-/-) mice. Our finding of cystatin C, elafin and fetuin-A as substrates and natural inhibitors for meprins reveal new mechanisms in the regulation of protease activity important for understanding pathophysiological processes.

The Territoriality of Fiscal Solidarity: Comparing Swiss Equalisation with European Union Structural Funding

This article theorises the territorial solidarity and fiscal federalism and compares Switzerland with the European Union. While inter-territorial solidarity is a prerequisite for legitimate fiscal equalisation, such equalisation in turn also contributes to the legitimacy of and solidarity within federal political systems. By cutting across territorial and ethno-national communities, fiscal transfers often contribute to both a “civic” sense of belonging and a “cosmopolitan” identity. After placing types and degrees of (inter-)territorial solidarity at the heart of our conceptual perspective, we discuss the effects of such solidarity through an analysis of two different forms of “federal” equalisation. Comparing the recently reformed Swiss fiscal equalisation system with the EU structural funds allows us to infer if, and how, the fiscal dimension of federalism matters for feelings of solidarity, reciprocity, unity and, ultimately, for the legitimacy of the very (nation-state or Union) structures that are to contribute to the ever-growing prosperity and happiness of their people(s). In Switzerland, a civic understanding of nationhood and cross-cutting cleavages were necessary conditions for extensive, effective and legitimate fiscal equalisation. We infer that, for the EU, this means that strengthening the equalisation component of the structural funds would contribute to an ever closer Union in a political sense: because fiscal equalisation and inter-territorial solidarity are interdependent, reinforcing the one also means cementing the other. Future studies of the EU and federal-type arrangements are advised to pay more explicit attention to the solidarity-element of territoriality – or the territoriality of (fiscal) solidarity.

Opting for an Open Society? Personality Traits and Attitudes toward the Openness of Switzerland

The tension between openness and closedness is one of the most important cleavages in Swiss political debates. In the present article, we study the psychological foundations of attitudes regarding this issue. More precisely, we examine the link between personality and attitudes toward the degree of openness of Switzerland as a general stance toward the cultural, economic and political alignment of the country. Personality is understood as a complex and multifaceted concept that forms the basis for consistent patterns of attitudes and behavior. We build on the Five-Factor Theory to explain the link between personality traits, contextual factors and political attitudes. Analyzing survey data from a random sample of Swiss citizens, we find clear evidence that personality traits affect political attitudes. Furthermore, we are able to demonstrate that the relationship between personality and attitudes toward the degree of openness of Switzerland is moderated by perceived ethnic diversity in the neighborhood.